Extended release formulation of levetiracetam

ABSTRACT

The present invention relates to extended release pharmaceutical compositions of Levetiracetam and processes for preparing the same. The extended release tablet of Levetiracetam is with a core comprising of Levetiracetam and water dispersible rate controlling polymer, and the tablet core is optionally functional coated comprising a combination of water non-dispersible and/or water dispersible polymer. It provides extended therapeutically effective plasma levels over a twenty four hour period with diminished incidences of neuropsychiatric adverse events by eliminating the troughs and peaks of drug concentration in a patient&#39;s blood plasma. The composition also exhibits no food effect.

This application is a continuation-in-part (CIP) of U.S. patentapplication Ser. No. 11/215,947, filed Aug. 31, 2005, which isincorporated herein by reference.

FIELD OF INVENTION

This invention relates to an extended release pharmaceutical compositionof Levetiracetam with once a day dosage regime and the process ofpreparing it.

BACKGROUND AND PRIOR ART

The use of high viscosity grade hydrophilic and the hydrophobic polymersto produce extended or controlled release pharmaceutical composition isknown in the art. For extending the release, the tablet comprising thedrug also comprises of high viscosity grade hydrophilic polymer. Ifrequired the tablets are coated with hydrophobic polymer and poreforming agent. As soon as the solid dosage form comes in contact withthe surrounding media, pores are formed and the drug is diffused throughthese pores. The media enters the tablet core and results into thehydration of the polymer which also controls the release of the drug.Control of the rate of release benefits therapy by producing constantblood plasma levels of the active ingredient and by decreasing thefrequency of administration, thereby improving the patient compliance tothe dosage regimen. The present invention provides a pharmaceuticalcomposition of extended release tablets of Levetiracetam suitable foronce daily administration to human subjects.

It is known that the absorption and bioavailability of any particulartherapeutic agent can be affected by numerous factors when dosed orally.Such factors include the presence of food in the gastrointestinal (GI)tract because, in general, the gastric residence time of a drug isusually significantly longer in the presence of food than in the fastedstate. If the bioavailability of a drug is affected beyond a certainpoint due to the presence of food in the GI tract, the drug is said toexhibit a “food effect”. Food effects are important inasmuch as, when adrug exhibits an adverse food effect, there is risk associated withadministering it to a patient who has eaten recently. The risk derivesfrom the potential that absorption into the bloodstream may be adverselyaffected to the point that the patient risks insufficient absorption toremediate the condition for which the drug was administered.

Levetiracetam is chemically named as (−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide with molecular formula C₈H₁₄N₂O₂ and molecular weight 170.21.Levetiracetam is white to off white crystalline powder and has aqueoussolubility of 104 gm/ml. It is freely soluble in chloroform (65.3 g/100mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL),sparingly soluble in acetonitrile (5.7 g/100 mL) and practicallyinsoluble in n-hexane. Levetiracetam is described in the U.S. Pat. Nos.4,837,223, 4,943,639 and 6,107,492.

Levetiracetam is indicated as adjunctive therapy in the treatment ofpartial onset seizures in adults with epilepsy. The precise mechanism(s)by which Levetiracetam exerts its antiepileptic effect is unknown anddoes not appear to derive from any interaction with known mechanismsinvolved in inhibitory and excitatory neurotransmission. Levetiracetamis rapidly absorbed with the oral bioavailability of 100%. Food does notaffect the extent of absorption of Levetiracetam but it decreases Cmaxby 20% and delays Tmax by 1.5 hours. The pharmacokinetics ofLevetiracetam are linear over a dose range of 500-5000 mg, with steadystate kinetics being achieved 2 days after multiple twice daily dosing.It is less than 10% bound to plasma proteins. Levetiracetam has plasmaelimination half life of 7±1 hr with the volume of distribution of 0.6L/Kg. The total body clearance is 0.9 ml/min/kg and the renal clearanceis 0.6 ml/min/kg. Its elimination is correlated with creatinineclearance. There is no age, gender, race or circadian effect.

Presently Levetiracetam is administered to adults as conventionalimmediate release tablets. The current dosing regimen includes twicedaily administration. Levetiracetam is available as an immediate releaseand is approved for sale in various countries including the UnitedStates of America under the brand name KEPPRA™ (UCB Pharma.). KEPPRA™ isavailable in 250, 500 and 750 mg strengths as the immediate releasetablet formulation.

In the Biopharmaceutics Classification System, it belongs to Class Isince it is highly soluble (1.04 g/ml), highly permeable (F>90%)and >85% of the tablet amount released in 15 minutes in three differentpH media. Clinically, it does not belong to narrow therapeutic classbecause it has a relatively low order of toxicity and a relatively hightherapeutic index.

The twice daily dosing regimen for immediate-release Levetiracetamtablets is well tolerated with few incidences of neuropsychiatricadverse events like, somnolence, fatigue, coordination difficulties andbehavioral abnormalities. The adverse effects are proportionate to thedrug plasma level and therefore for improving the therapeutic efficacy,reducing incidences of adverse events and enhancing patient compliancean extended release once-daily regimen is explored in the presentinvention.

WO 01/51033 provides for a Solid pharmaceutical compound that can beadministered orally, permitting controlled release of at least oneactive substance which can be Levetiracetam consisting of a homogeneousmixture comprising active substance, at least one matrix excipientbetween 5 and 95% by weight in relation to total weight of the compound,selected among the inert matrices, the hydrophilic, or lipid matrices,mixtures of inert and lipidic matrices mixture of hydrophilic and inertmatrices; at least one entero-soluble polymer between 2 and 50% byweight in relation to the total weight of the compound and at least onealkalinizing agent soluble in a aqueous phase under conditions ofphysiological pH, of at least 0.5 to 50% by weight in relation to thetotal weight of the compound.

WO 03/101428 provides for a method for the manufacture of apharmaceutical compound with retarded release of the active principle,which can be Levetiracetam. A mixture of active substance and thepolymer that provides the retarded release are compressed by puttingthem through two rollers that have a temperature of more than 40° C. andcompaction force is exerted on it of more than 15 to 40 kN/cm rollerwidth. The compressed mixture is powdered to the desired particle sizeand if required the process is repeated.

OBJECTIVES OF INVENTION

The object of the present invention is to provide an extended releasepharmaceutical composition of Levetiracetam, which upon ingestionresults in blood plasma levels having plateau effect, for an extendedperiod of time

Another object of the present invention is to produce a pharmaceuticalcomposition which releases Levetiracetam in predetermined manner.

Yet another object of the present invention is to provide extendedrelease pharmaceutical composition of Levetiracetam for once dailydosage regimen.

Yet another object of the present invention is to provide a extendedrelease composition of Levetiracetam which does not exhibit food effect.

Yet another object of the present invention is to provide an extendedrelease composition of Levetiracetam which shows reduced inter subjectvariability.

SUMMARY OF THE INVENTION

The present invention relates to compositions of and processes ofpreparing an extended release pharmaceutical composition ofLevetiracetam which comprises Levetiracetam, optionally a binder,hydrophilic rate controlling polymer and conventional pharmaceuticallyacceptable excipients, the blend is compressed into a tablet and theformed tablet is further coated with a functional coating comprising ofa hydrophobic rate controlling polymer. The functional coatingoptionally comprises of a channeling agent which can be a hydrophilicpolymer or a water soluble substance. The composition may be furthercoated with a polymer based non functional coating. The components areselected in such a way to give extended release of Levetiracetam in apredetermined manner.

Preferably, the present invention relates to the extended releaseformulation which comprises from about 30% w/w to about 85% w/w ofLevetiracetam, from about 1% w/w to about 50% w/w of hydrophilic polymerand optionally from about 1% w/w to about 10% w/w binder. All theseweights are in relation to the weight of the core tablets. The tablet isfurther functional coated with a hydrophobic polymer, which comprises ofabout 2% w/w to about 15% w/w of the weight of core tablet. The coatingoptionally comprises channeling agent from about 10% w/w to about 60%w/w of the total weight of the coating layer. Further the coated tabletis given a nonfunctional coating which comprises about 1% w/w to 3% w/wof the total weight of the composition.

More preferably the present invention relates to the extended releaseformulation which comprises from about 50% w/w to about 75% w/w ofLevetiracetam, from about 0.5% to about 5% Polyvinyl pyrrolidone, fromabout 20% w/w to about 45% w/w Hydroxypropyl Methylcellulose. Thefunctional coating on the tablets comprises of from about 2% w/w toabout 5% w/w of the total weight of the composition. The coatingcomprises from about 50% w/w to about 80% w/w ethyl cellulose asfunctional polymer and from about 15% w/w to about 35% w/w HydroxypropylMethylcellulose, as a channeling agent.

According to the present invention, the extended release formulation isprepared by compression of a matrix tablet followed by functionalcoating, the said method comprising steps of:

-   -   i. Blending Levetiracetam or its granules prepared by dry or wet        granulation with the rate controlling polymer.    -   ii. Lubricating the blended mixture and compressing into tablets        of appropriate shape.    -   iii. Coating the tablets with an aqueous dispersion of water        insoluble and water soluble polymer.    -   iv. Coating the tablets with an aqueous dispersion of the        nonfunctional coating polymer.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a plot showing the drug release profile of Levetiracetam fromfour different compositions of the drug in matrices using USP I, 100 rpmand at 37° C.

FIG. 2 is a plot showing the comparative plasma level profile ofLevetiracetam under Fed dosing in Healthy Human volunteers.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, the extended release tabletcomprises of active ingredient and water soluble rate controllingpolymer and optionally conventional excipients including a binder. Thesetablets are coated with a combination of water insoluble polymer. Thecoating optionally includes a water soluble polymer or substance as achanneling agent. The functional coated tablets are further coated withwater soluble polymer as non functional coat.

According to the embodiment of the present invention the activeingredient is used as such, inclusive or exclusive of the binder, if thecrystal morphology is favoring direct compression. However, if theparticles are not favoring direct compression and granulation isrequired then it is carried out either as ‘dry granulation’ or as ‘wetgranulation’. The dry granulation process involves the mixing of drugwith the binder or directly with the rate controlling hydrophilicpolymer or both, followed by slug formation on tablet press or using theroll compactors. The process of wet granulation includes aqueous or nonaqueous granulation. The wet granulation process comprises the admixingof the active ingredient with ‘diluent’ or mixture of ‘diluent’ and ratecontrolling hydrophilic polymer, and granulation of the blend with thebinder mass to form the wet mass followed by drying and sizing. Thebinder may optionally be admixed with the dry blend and granulationperformed with aqueous or non aqueous solvent. The solvent for the nonaqueous granulation is selected from ethanol, isopropyl alcohol anddichloromethane.

According to the present invention, the pharmaceutical compositioncontains Levetiracetam as an active ingredient. The Levetiracetam may bepresent in an amount from about 40% to about 80%, more preferably formabout 50% to about 75% by weight of extended release composition.

In the preferred embodiment of the present invention Levetiracetam isgranulated using aqueous granulation with a binder solution. The binderused is essentially important to impart compressibility, flow propertyand strength/hardness. The binder can be selected from Polyvinylpyrrolidone, Hydroxypropyl cellulose, Hydroxypropyl Methylcellulose (lowviscosity grade), methyl cellulose, starch, pregelatinized starch,modified corn starch, polyacryl amide, poly-N-vinyl amide, sodiumcarboxymethyl cellulose, polyethylene glycol, gelatin, polyethyleneoxide, poly propylene glycol, tragacanth, alginic acid, combinationsthere of and other materials known to one of ordinary skill in the art.The binder may be present in an amount from about 0.01% to about 10%,preferably from about 0.5% to about 5% by weight of the extended releasecomposition.

According to the embodiment of the present invention the active granulesare blended with hydrophilic rate controlling polymer of high viscositygrade as a part of the matrix system. The high viscosity grade is theone which provide viscosity greater than 15 cps in a 2% w/w solution.The hydrophilic rate controlling polymer in the matrix system includesHydroxyethyl cellulose, Hydroxypropyl cellulose, sodium alginate,carbomer (Carbopol™), sodium carboxymethyl cellulose, xanthan gum, guargum, locust bean gum, poly vinyl acetate, polyvinyl alcohol andHydroxypropyl Methylcellulose (high viscosity grade). The matrix formingpolymer comprises from about 1% to about 50%, preferably from about 20%to about 40% by weight of the coated extended release composition.

In yet another embodiment the present invention discloses an extendedrelease pharmaceutical composition of levetiracetam which does notexhibit a food effect. The present invention provides an extendedrelease compositions of Levetiracetam which can be administered to amammal (including humans) in fed state and which exhibits a mean(AUC_(fasting))/(AUC_(fed)) of at least 0.80. In particular, the presentinvention provides an extended release compositions of Levetiracetamwhich can be administered to a mammal (including humans) in fed stateand which exhibits a mean (AUC_(fasting))/(AUC_(fed)) of at least 0.80and/or with a lower 90% confidence limit of at least 0.75.

According to the embodiment of the present invention, for definitionalpurposes, and specifically with respect to Levetiracetam extendedrelease compositions only, a dosage form of Levetiracetam exhibits afood effect if, after dosing a population, once fasted and once fed, themean (AUC_(fasting))/(AUC_(fed)) is below the value 0.80 and/or thelower 90% confidence limit for this ratio is below 0.75. Conversely, adosage form of Levetiracetam which does not exhibit a food effect is onewhich, when tested on a test population, exhibits a value for(AUC_(fasting))/(AUC_(fed)) of at least 0.80 and/or a lower 90%confidence limit for this value is at least 0.75. The value for mean(AUC_(fasting))/(AUC_(fed)) can be any value above 0.80 and still bewithin the scope of this invention, though it is preferred that it canhave an upper (mean) limit of 1.25, and/or an upper 90% confidence limitof 1.40 or below.

In addition to the above ingredients the extended release tablets asdescribed here also contains the lubricant, anti adherent and a glidant.Antiadherents include, by way of example and without limitation,magnesium stearate, talc, calcium stearate, glyceryl behenate,Polyethylene glycols, hydrogenated vegetable oil, mineral oil, stearicacid and other materials known to one of ordinary skill in the art.Glidants include cornstarch, talc, calcium silicate, magnesium silicate,colloidal silicon dioxide, silicon hydrogel and other materials known toone of ordinary skill in the art. Lubricants include, by way of exampleand without limitation, calcium stearate, magnesium stearate, sodiumstearyl fumerate, glyceryl palmitostearate, glyceryl stearate, mineraloil, stearic acid, and zinc stearate and other materials known to one ofordinary skill in the art. The glidants, lubricants and anti adherentsare individually present in the range from about 0.01% to about 5% w/wof the coated tablets. Preferably the glidants, anti adherents andlubricants are present in the range from about 0.5% to about 4% weightof the coated tablets, either alone or in combination.

The formed extended release tablets are coated with a hydrophobic ratecontrolling polymeric coat and the rate controlling polymeric coat iscomposed of hydrophobic polymer, hydrophobic or hydrophilic plasticizerand/hydrophilic pore forming polymer (channeling agent). The hydrophobicfilm forming polymer is selected from the group consisting of celluloseether such as ethyl cellulose, cellulose acetate, polyvinyl acetate,methacrylic acid esters neutral polymer, polyvinyl alcohol-maleicanhydride copolymers and the like. Even the commercially availabledispersion of film formers namely, Eudragit L-30D, Eudragit NE 30D,Aquacoat ECD-30, Surelease E-7, Eudragit RS 30D, Eudragit RL 30D, etc.may be used for the purpose of providing rate controlling coat. Thehydrophilic pore forming polymer in the rate controlling coat is said tobe selected from copolyvidone, Polyvinyl pyrrolidone, polyethyleneglycols, Hydroxyethyl cellulose, Hydroxypropyl Methylcellulose (lowviscosity grade). In the current embodiment, the water insoluble polymeris present in an amount from 40% to about 90%, preferably from about 50%to about 80% by weight of the functional coating layer of extendedrelease composition. The water soluble pore forming polymer is presentin an amount from about 10% to about 60%, preferably from about 15% toabout 35% by weight of the coating layer. Additionally the coatingdispersion may also comprise of plasticizer to modify the properties andcharacteristics of the polymers used on the coat of the compressedtablets. Plasticizers useful in the invention can include, by way ofexample and without limitation, low molecular weight polymers,oligomers, copolymers, oils, small organic molecules, low molecularweight polyols having aliphatic hydroxyls, ester-type plasticizers,glycol ethers, poly(propylene glycol), multi-block polymers, singleblock polymers, low molecular weight poly(ethylene glycol), citrateester-type plasticizers, triacetin, propylene glycol and glycerin. Suchplasticizers can also include ethylene glycol, 1,2-butylene glycol,2,3-butylene glycol, styrene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol and other poly(ethylene glycol) compounds,monopropylene glycol monoisopropyl ether, propylene glycol monoethylether, ethylene glycol monoethyl ether, diethylene glycol monoethyl,ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,dibutylsebacate, acetyltributylcitrate, triethyl citrate, acetyltriethyl citrate, tributyl citrate and allyl glycolate. Also thecombination of the plasticizers can be used in the present formulation.The composition in the present embodiment preferably comprises 1.0 to10.0% of hydrophobic polymer per weight of the coated tablets;optionally up to 5% per weight of hydrophilic pore forming polymer ofthe coated tablets and optionally up to 2% of plasticizer per weight ofthe coated tablets.

According to the present invention, the non-functional coating isselected from the group of ready to form dispersion such as OPADRY. TheOPADRY comprises of the hydrophilic (low viscosity grade) film formingpolymer, suitable colorant and the opacifying agent. Opacifying agentinclude by titanium dioxide and other materials known to one of ordinaryskill in the art. Colorant include, by way of example and withoutlimitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&CBlue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel,and ferric oxide, red, other F.D. & C. dyes and natural coloring agentssuch as grape skin extract, beet red powder, beta-carotene, annato,carmine, turmeric, paprika, and other materials known to one of ordinaryskill in the art.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. The following examples aregiven to illustrate the present invention. It should be understood thatthe invention is not to be limited to the specific conditions or detailsdescribed in these examples

Examples 1-2

TABLE 1 Composition Sr. Weight in mgs No. Ingredient Ex. 1 Ex. 2 1Levetiracetam 500.00 500.00 2 Povidone 05.00 05.00 3 Purified water q.s.q.s. 4 Hydroxypropyl Methylcellulose (HV) 300.00 300.00 5 MagnesiumStearate 10.00 10.00 6 Colloidal silicon dioxide 5.00 5.00 7 Aqueousdispersion of Ethyl cellulose — 24.30 (solid content) Total 820 844.30q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s. s. sieve of mesh 40 and wasthen granulated with aqueous Polyvinyl pyrrolidone solution and thegranulated mass was dried at 50° C. The dried granules were sizedthrough s. s. sieve of 20 mesh and these granules were blended withHydroxypropyl Methylcellulose, lubricated with magnesium stearate andcolloidal silicon dioxide and the lubricated granules were compressedinto tablets.

As mentioned in Table 1 the tablets of example 2 were further coatedwith aqueous dispersion of hydrophobic rate controlling ethyl celluloseto weight gain of 2.96% w/w of the compressed tablet. Following thefunctional coating the tablets were cured at 55° C. for 1 hour.

Example 3

TABLE 2 Composition Sr. Weight in mgs No. Ingredient Ex. 3 1Levetiracetam 500.00 2 Povidone 05.00 3 Purified water q.s. 4Hydroxypropyl Methylcellulose (HV) 300.00 5 Magnesium Stearate 10.00 6Colloidal silicon dioxide 5.00 7 Aqueous dispersion of Ethyl cellulose35.82 (solid content) 8 Opadry 42.98 Total 898.80 q.s. means quantitysufficient.

Levetiracetam 500 mg was sifted through s. s. sieve of mesh 40 and wasthen granulated with aqueous Polyvinyl pyrrolidone solution and thegranulated mass was dried at 50° C. The dried granules were sizedthrough s. s. sieve 20 mesh and these granules were blended withHydroxypropyl Methylcellulose, lubricated with magnesium stearate andcolloidal silicon dioxide and lubricated granules were compressed intotablets. The compressed tablets were coated with the mixture of aqueousdispersion of ethyl cellulose and Opadry to a weight gain of 9.60% w/wof the compressed tablets. Following the functional coating the tabletswere cured at 55° C. for 1 hour.

Example 4

TABLE 3 Composition Sr. Weight in mgs No. Ingredient Ex. 4 1Levetiracetam 500.00 2 Povidone 10.00 3 Purified water q.s. 4Hydroxypropyl Methylcellulose (HV) 285.00 5 Magnesium Stearate 10.00 6Colloidal silicon dioxide 5.00 7 Opadry 16.30 8 Talc 5.00 Total 831.30q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s. s. sieve of mesh 40 and wasthen granulated with aqueous Polyvinyl pyrrolidone solution and thegranulated mass was dried at 50° The dried granules were sized throughs. s. sieve of 20 mesh and these granules were blended withHydroxypropyl Methylcellulose, lubricated with magnesium stearate, talcand colloidal silicon dioxide and lubricated granules were compressedinto tablets. The compressed tablets were coated with Opadry to a weightgain of 2% w/w of the compressed tablets.

Examples 5-6

TABLE 4 Composition Sr. Weight in mgs No. Ingredient Ex. 5 Ex. 6 1Levetiracetam 500.00 500.00 2 Povidone 10.00 10.00 3 Purified water q.s.q.s. 4 Hydroxypropyl Methylcellulose (HV) 285.00 285.00 5 MagnesiumStearate 10.00 10.00 6 Colloidal silicon dioxide 5.00 5.00 7 Aqueousdispersion of Ethyl cellulose 15.28 30.56 (solid content) 8 Opadry 16.7117.12 9 Talc 5.00 5.00 10 Hydroxypropyl Methylcellulose (LV) 5.10 10.19Total 852.09 872.87 q.s. means quantity sufficient.

Levetiracetam 500 mg was sifted through s.s. sieve of mesh 40 and wasthen granulated with aqueous Polyvinyl pyrrolidone solution and thegranulated mass was dried at 50° C. The dried granules were sizedthrough s. s. sieve of 20 mesh and these granules were blended withHydroxypropyl Methylcellulose, lubricated with magnesium stearate, talcand colloidal silicon dioxide and the lubricated granules werecompressed into tablets.

The tablets of example 5 and 6, as mentioned in the table 4, were coatedwith mixture of aqueous dispersion of ethyl cellulose and HydroxypropylMethylcellulose (LV; low viscosity) in the ratio of 75:25 (solidcontent). The tablets were coated to target weight gain of 2.5% w/w and5.0% w/w of the compressed tablets for example 5 and example 6respectively. Following the coating the tablet were cured at 65° C. for1 hr.

The coated tablets were further coated with Opadry to a weight gain of2% w/w of the functional coated tablet.

Example 7

The extended release tablets of Examples 1 to Example 6 were tested fordissolution of Levetiracetam using 900 ml of pH 6.8 phosphate buffer asdissolution media at 37° C. and in 40-mesh basket (USP Type 1) at 100rpm

The dissolution profiles are recorded in Table 5.

TABLE 5 Dissolution Profile Percentage Levetiracetam dissolved Time(hrs) Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 1 26 0 16 30 16 10 2 40 3 3043 30 23 3 51 7 41 53 41 34 4 60 14 51 61 51 43 6 75 27 67 74 66 58 8 8841 81 83 80 69 10 98 54 94 90 90 78 12 105 66 103 94 99 85

Example 8

TABLE 6 Composition Sr. Weight in mgs No. Ingredient Ex. 8 1Levetiracetam 750.00 2 Povidone 15.00 3 Purified water q.s. 4Hydroxypropyl Methylcellulose (HV) 316.00 5 Magnesium Stearate 12.00 6Colloidal silicon dioxide 6.00 7 Talc 6.00 8 Aqueous dispersion of Ethylcellulose 16.58 (solid content) 9 Opadry 22.54 10 HydroxypropylMethylcellulose (LV) 5.52 Total 1149.64 q.s. means quantity sufficient.

Levetiracetam 750 mg was sifted through s. s. sieve of mesh 40 and wasthen granulated with aqueous Polyvinyl pyrrolidone solution and thegranulated mass was dried at 50° C. The dried granules are sized throughs. s. sieve of 20 mesh and these granules were blended withHydroxypropyl Methylcellulose and then lubricated with magnesiumstearate, colloidal silicon dioxide and talc and the lubricated granuleswere compressed into tablets.

The tablets as mentioned in the table 6, were coated with mixture ofaqueous dispersion of ethyl cellulose and Hydroxypropyl MethylcelluloseLV in the ratio of 75:25 (solid content). The tablets were coated totarget weight gain of 2.0% w/w. Following the coating the tablet werecured at 65° C. for 1 hr.

The coated tablets were further coated with Opadry to a weight gain of2% w/w of the functional coated tablet.

Example 9

TABLE 7 Composition Sr. Weight in mgs No. Ingredient Ex. 9 1Levetiracetam 750.00 2 Carbopol (71 G) 330 3 Glyceryl Behenate 15 4Colloidal silicon dioxide 5 5 Talc 5 Total 1105 q.s. means quantitysufficient.

Levetiracetam 750 mg and carbopol were sifted through s. s. sieve ofmesh 30 and were blended together. The blend was lubricated withglyceryl behenate, colloidal silicon dioxide and talc and the lubricatedblend was compressed into tablets.

Example 10

TABLE 8 Composition Sr. Weight in mgs No. Ingredient Ex. 10 1Levetiracetam 750.00 2 Polyvinyl Acetate 275 3 Glyceryl Behenate 15 4Colloidal silicon dioxide 5 5 Talc 5 6 Aqueous dispersion of Ethylcellulose 15.00 (solid content) 7 Opadry 20 8 HydroxypropylMethylcellulose (LV) 5 Total 1145 q.s. means quantity sufficient.

Levetiracetam 750 mg and Kollidon SR (Polyvinyl Acetate: PolyvinylPyrolidone, 8:2) were sifted through s. s sieve of mesh 30 and blendedtogether. The blend was lubricated with glyceryl behenate, colloidalsilicon dioxide and talc and the lubricated blend was compressed intotablets.

The tablets as mentioned in the table 8, were coated with mixture ofaqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose(LV) in the ratio of 75:25 (solid content). The tablets were coated totarget weight gain of 1.90% w/w of the uncoated tablets. Followingcoating the tablet were cured at 65° C. for 1 hr.

The functional coated tablets were further coated with Opadry to aweight gain of 1.87% w/w of the functional coated tablet.

Example 11

TABLE 9 Composition Sr. Weight in mgs No. Ingredient Ex. 11 1Levetiracetam 750.00 2 Hydroxypropyl Methylcellulose (HV) 350 3Magnesium stearate 12.00 4 Colloidal silicon dioxide 6.00 5 Talc 6.00 6Aqueous dispersion of Ethyl cellulose 15.00 (solid content) 7 Opadry 208 Hydroxypropyl Methylcellulose (LV) 5 Total 1164 q.s. means quantitysufficient.

Levetiracetam 750 mg and hydroxyl propyl methyl cellulose (HV) weresifted through s. s. sieve of mesh 40 and blended together. The blendwas compacted using a roll compactor (Chilsonator) to form slugs. Theslugs were sized in an oscillating granulator using a s. s. sieve ofmesh 20. Obtained granules were lubricated with magnesium stearate,colloidal silicon dioxide and talc. The lubricated blend was compressedinto tablets.

The tablets as mentioned in the table 9 were coated with mixture ofaqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose(LV) in the ratio of 75:25 (solid content). The tablets were coated totarget weight gain of 1.78% w/w of the uncoated tablets. Following thecoating the tablet were cured at 65° C. for 1 hr.

The functional coated tablets were further coated with Opadry to aweight gain of 1.75% w/w of the functional coated tablet.

Example 12

TABLE 10 Composition Sr. Weight in mgs No. Ingredient Ex. 12 1Levetiracetam 750.00 2 Hydroxypropyl Methylcellulose (HV) 271 3Hydroxypropyl cellulose 45.00 4 Magnesium stearate 12.00 5 Colloidalsilicon dioxide 6.00 6 Talc 6.00 7 Aqueous dispersion of Ethyl cellulose15.00 (solid content) 8 Opadry 20 9 Hydroxypropyl Methylcellulose (LV) 5Total 1164 q.s. means quantity sufficient

Levetiracetam 750 mg and Hydroxylpropyl Methylcellulose (HV) were siftedthrough s. s. sieve of mesh 40 and blended together. The blend wasgranulated using nonaqueous granulation using Hydroxypropyl Cellulose asthe binder. The granulated mass was dried at 45° C. The dried granuleswere sized through s. s. sieve of mesh 20 and the granules werelubricated with Magnesium Stearate, Talc and Colloidal Silicon dioxide.The lubricated blend was compressed into tablets.

The tablets as mentioned in the table 10 were coated with mixture ofaqueous dispersion of ethyl cellulose and Hydroxypropyl MethylcelluloseLV in the ratio of 75:25 (solid content). The tablets were coated totarget weight gain of 1.78% w/w of the uncoated tablets. Following thecoating the tablet were cured at 65° C. for 1 hr.

The coated tablets were further coated with Opadry to a weight gain of1.75% w/w of the functional coated tablet.

Example 13

TABLE 11 Composition Sr. Weight in mgs No. Ingredient Ex. 13 1Levetiracetam 750.00 2 Hydroxypropyl cellulose 45.00 3 Hydroxyethylcellulose (HV) 271 4 Magnesium stearate 12.00 5 Colloidal silicondioxide 6.00 6 Talc 6.00 7 Aqueous dispersion of Ethyl cellulose 15.00(solid content) 8 Opadry 20 9 Hydroxypropyl Methylcellulose (LV) 5 Total1164 q.s. means quantity sufficient.

Levetiracetam 750 mg was sifted through s. s. sieve of mesh 40 and wasthen granulated with non aqueous Hydroxypropyl cellulose solution andthe granulated mass was dried at 45° C. The dried granules are sizedthrough s. s. sieve of mesh 20 and these granules were blended withHydroxyethyl cellulose and lubricated with magnesium stearate, colloidalsilicon dioxide and talc. The lubricated granules were compressed intotablets.

The tablets as mentioned in the table 11, were coated with mixture ofaqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose(LV) in the ratio of 75:25 (solid content). The tablets were coated totarget weight gain of 1.78% w/w. The coated tablet were cured at 65° C.for 1 hr.

The functional coated tablets were further coated with Opadry to aweight gain of 1.75% w/w of the functional coated tablet.

Example 14

The extended release tablets of Examples 8 to Example 13 were tested fordissolution of Levetiracetam using 900 ml of pH 6.8 phosphate buffer asdissolution media at 37° C. and in 40-mesh basket (USP Type 1) at 100rpm

The dissolution profiles are recorded in Table 12.

TABLE 12 Dissolution Profile Percentage Levetiracetam dissolved Time(hrs) Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 1 17 23 9 18 6 6 2 30 4426 33 12 30 3 41 59 45 45 22 48 4 49 72 59 55 31 60 6 63 91 78 72 49 828 76 101 93 85 66 94 10 85 99 98 95 79 99 12 91 98 97 101 91 97

Example 15

An in vivo study was conducted in healthy human volunteers to assessbioavailability of Levetiracetam formulated as the extended releasetablets of Example 8 by comparison with a reference treatment withimmediate release Levetiracetam tablets.

Method

The study followed an open label, two-treatment, two-periods,comparative oral bioavailability study in healthy, adult, male, humansubjects under fed conditions. The subjects received each of the twotreatments during the course of the study, which was conducted at asingle center. The subjects were given 1500 mg oral dose ofLevetiracetam. In the case of the IR formulation, which was provided asKeppra® tablets, two equally divided doses of 750 mg each were given at12 hour interval beginning in the morning. In the case of the extendedrelease formulation of Example 8, two tablets of 750 mg were given at atime in the morning. Plasma Levetiracetam concentrations were quantifiedby HPLC method. Samples were not diluted prior to analysis as all sampleconcentrations were within the limits of quantitation. Pharmacokineticparameters for Levetiracetam were estimated by non compartmentalmethods. The parameters Tmax, Cmax, AUC_(0→t), AUC_(0→∞) were estimatedduring the studies and recorded in Table 13.

Results

Mean plasma Levetiracetam concentrations over the 36 hour assessmentperiod are shown in FIG. 2.

TABLE 13 Formulation of Keppra Parameter Unit Example 8 tablets 750 mgCmax μg/ml 17.194 ± 4.23   22.23 ± 5.44 Tmax Hrs 12-13 2-3 and 14-15 AUC(0→t) ug · h/mL  345.81 ± 105.45 375.267 ± 76.86 AUC (0→inf) μg · h/mL383.855 ± 125.87 413.854 ± 91.50

Example 16-18

TABLE 14 Composition Sr. Weight in mgs No Ingredient Ex. 16 Ex. 17 Ex.18 1 Levetiracetam 750.00 500.00 1000 2 Povidone USP 10.00 10.00 20(Plasdone K 90 D) 3 Purified water q.s. q.s. q.s. 4 Hypromellose 2208(Methocel 250.00 167.00 333 K100M CR) USP 5 Hypromellose 2208 (Methocel41.00 27.00 55 K100 LV) USP 6 Colloidal silicon dioxide 6 4 8 7Magnesium Stearate NF 12 8 16 8 Talc BP 6 4 8 9 Ethyl cellulose 7 cps19.65 13.10 26.20 10 Polyethyleneglycol 4000 7.56 5.04 10.08 11 MethocelE-3 (Hypermellose 2910) 10.58 7.06 14.12 Total 1117.80 745.20 1490.4q.s. means quantity sufficient.

Levetiracetam 750 mg was sifted through s. s. sieve of mesh 40 and wasthen granulated with aqueous Polyvinyl pyrrolidone solution and thegranulated mass was dried at 45° C. The dried granules are sized throughs. s. sieve of mesh 20 and these granules were blended with Hypermellose2208 and lubricated with magnesium stearate, colloidal silicon dioxideand talc. The lubricated granules were compressed into tablets.

The tablets as mentioned in the table 14, were coated with mixture ofaqueous dispersion of ethyl cellulose and Hydroxypropyl Methylcellulose(E-3) and polyethylene glycol. The tablets were coated to target weightgain of 3.5% w/w. The coated tablets were cured at 65° C. for 1 hr.

The functional coated tablets were further coated with Opadry to aweight gain of 2.5% w/w of the functional coated tablet.

Example 19

The extended release tablets of Examples 16-18 were tested fordissolution of Levetiracetam using 900 ml of pH 6.8 phosphate buffer asdissolution media at 37° C. and in 40-mesh basket (USP Type 1) at 100rpm

The dissolution profiles are recorded in Table 15.

TABLE 15 Dissolution Profile Percentage Levetiracetam dissolvedTime(hrs) Ex. 16 Ex. 17 Ex. 18 1 20 16 14 2 35 31 29 3 46 44 39 4 55 5349 6 69 67 63 8 79 77 72 10 87 86 80 12 93 91 86

A randomized two-treatment, two period, cross-over pharmacokinetic studywas conducted in eighteen healthy, adult, male human subjects in bothfast and fed conditions for the above formulations and the data obtainedwas compared with the data of Keppra® tablets.

Results

The following are a tabulation of the results of the study in both fastand fed conditions. Comparison of data of the Tablet of Example 16 andKeppra tablets in fasting conditions

TABLE 16 Parameter Unit Keppra ™ Example 16 Cmax ng/ml 31.49 ± 5.3420.46 ± 2.08 Tmax Hrs 13.01 ± 0.55  9.88 ± 2.39 AUC (0-t) ng · h/mL469.98 ± 35.50 432.098 ± 55.11  AUC (0-inf) ng · h/mL 516.99 ± 46.03462.93 ± 65.25

Comparison of data of the invention of Example 16 and Keppra tablets infed conditions

TABLE 17 Parameter Unit Keppra ® Example 16 Cmax ng/ml 27.22 ± 3.4320.50 ± 3.32 Tmax Hrs 12.59 ± 4.48 13.22 ± 2.81 AUC (0-t) ng · h/mL461.31 ± 57.66 450.12 ± 62.65 AUC (0-inf) ng · h/mL 507.78 ± 75.20497.27 ± 73.63

As can be seen from the above data, the AUC_(fasted)/AUC_(fed) forexample 16 is 0.96 for AUC_((0-t)) and 0.93 for AUC_((0-inf)).

Although certain presently preferred embodiments of the invention havebeen specifically described herein, it will be apparent to those skilledin the art to which the invention pertains that variations andmodifications of the various embodiments shown and described herein maybe made without departing from the spirit and scope of the invention.Accordingly, it is intended that the invention be limited only to theextent required by the appended claims and the applicable rules of law.

We claim:
 1. An extended release tablet of Levetiracetam comprising fromabout 30% to about 85% w/w of the tablet of Levetiracetam and about 1%to about 50% w/w of the tablet of a water dispersible rate controllingpolymer, which exhibits no adverse food effect.
 2. An extended releasetablet formulation according to claim 1, wherein said tablet exhibitinga value of (AUC_(fed))/(AUC_(fasted)) of at least 0.80 with a lower 90%confidence limit of at least 0.75.
 3. An extended release tabletformulation according to claim 1, wherein said tablet is coated with afunctional coat of about 1% to 15% w/w of the tablet weight comprising acombination of a water non-dispersible polymer and a water dispersiblepolymer.
 4. An extended release tablet formulation according to claim 1,wherein when orally administered to a patient in need thereof provides apeak plasma level of Levetiracetam in from about eight to about sixteenhours and provides extended therapeutically effective plasma levels overa twenty four hour period with diminished incidences of neuropsychiatricadverse events by eliminating the troughs and peaks of drugconcentration in vivo.
 5. An extended release tablet according to claim1, wherein the tablet is comprised of from about 50% to 80%Levetiracetam w/w of the tablet and about 20% to about 40% w/w of thetablet hydroxypropyl methylcellulose.
 6. An extended release tabletaccording to claim 5, wherein the tablet further comprises about 1% toabout 5% w/w of the tablet povidone.
 7. An extended release tabletaccording to claim 6, wherein the tablet is coated with a functionalcoat comprising ethyl cellulose, hydroxypropyl methylcellulose andpolyethylene glycol.
 8. An extended release tablet according to claim 1,wherein the tablet is coated with a functional coat of about 1% to about12% w/w of the tablet weight, said functional coat comprising of fromabout 70% to about 80% w/w of the functional coat of ethyl cellulose,from about 20% to about 30% w/w of the functional coat of hydroxypropylmethylcellulose and from 10 to about 20% w/w of the functional coat ofpolyethylene glycol.
 9. An extended release tablet according to claim 1wherein the tablet is coated with a functional coat of about 1% w/w toabout 12% w/w of the tablet weight, said functional coat comprising offrom about 70% to about 80% w/w of the functional coat of ethylcellulose and from about 20% to about 30% w/w of the functional coat oflactose.
 10. An extended release tablet according to claim 1 having thefollowing dissolution profile in USP Apparatus 1 (basket) at 100 rpm inpurified water at 37° C.: Time (hours) Average % Levetiracetam released2 <35 4 35-75 12 >75


11. An extended release tablet according to claim 1, wherein the tabletis comprised of from about 61% to 73% w/w of the tablet levetiracetamand about 25% to about 35% w/w of the tablet. hydroxypropylmethylcellulose
 12. An extended release tablet according to claim 11,wherein the tablet further comprises from about 1.1% to about 1.5% w/wof the tablet povidone.
 13. An extended release tablet according toclaim 11, wherein the tablet is coated with a functional coat of about1.0% to about 6.0% w/w of the tablet, said functional coat comprising ofabout 75% w/w of the functional coat of ethyl cellulose and about 25%w/w of the functional coat of hydroxypropyl methylcellulose.
 14. Anextended release tablet according to claim 11, wherein the tablet iscoated with a functional coat comprising of ethyl cellulose,hydroxypropyl methylcellulose and polyethylene glycol.
 15. An extendedrelease tablet according to claim 1, wherein said tablet is coated witha functional coat of about 1-6% w/w of the tablet.
 16. An extendedrelease tablet according to claim 15, wherein the functional coatcomprises of ethyl cellulose having a 44.0-51.0% content of ethoxygroups and hydroxypropyl methylcellulose having viscosity of 2-6 cps at2% aqueous solution with a methoxy content of 28.0-30.0% and ahydroxypropoxy group content of 7.0-12.0%.
 17. An extended releasetablet according to claim 1, wherein the tablet is prepared by wetgranulation, dry granulation or direct compression.
 18. An extendedrelease tablet according to claim 1, wherein the tablet is prepared bywet granulation, dry granulation or direct compression and the core iscoated either in a coating pan or in a fluidized bed system.
 19. Theextended release tablet of claim 1 wherein the hydrophilic polymer is inthe form of Opadry ready mix.